Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway

L Pirkkala, T P Alastalo, X Zuo, I J Benjamin, L Sistonen

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Inhibition of proteasome-mediated protein degradation machinery is a potent stress stimulus that causes accumulation of ubiquitinated proteins and increased expression of heat shock proteins (Hsps). Hsps play pivotal roles in homeostasis and protection in a cell, through their well-recognized properties as molecular chaperones. The inducible Hsp expression is regulated by the heat shock transcription factors (HSFs). Among mammalian HSFs, HSF1 has been shown to be important for regulation of the heat-induced stress gene expression, whereas the function of HSF2 in stress response is unclear. Recent reports have suggested that both HSF1 and HSF2 are affected during down-regulation of ubiquitin-proteasome pathway (Y. Kawazoe et al., Eur. J. Biochem. 255:356-362, 1998; A. Mathew et al., Mol. Cell. Biol. 18:5091-5098, 1998; D. Kim et al., Biochem. Biophys. Res. Commun. 254:264-268, 1999). To date, however, no unambiguous evidence has been presented as to whether a single specific HSF or multiple members of the HSF family are required for transcriptional induction of heat shock genes when proteasome activity is down-regulated. Therefore, by using loss-of-function and gain-of-function strategies, we investigated the specific roles of mammalian HSFs in regulation of the ubiquitin-proteasome-mediated stress response. Here we demonstrate that HSF1, but not HSF2, is essential and sufficient for up-regulation of Hsp70 expression during down-regulation of the ubiquitin proteolytic pathway. We propose that specificity of HSF1 could be an important therapeutic target during disease pathogenesis associated with abnormal ubiquitin-dependent proteasome function.

Original languageEnglish
Pages (from-to)2670-5
Number of pages6
JournalMolecular and Cellular Biology
Volume20
Issue number8
DOIs
Publication statusPublished - Apr 2000
MoE publication typeA1 Journal article-refereed

Keywords

  • Cysteine Endopeptidases/genetics
  • DNA-Binding Proteins/genetics
  • Gene Expression Regulation
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins/genetics
  • Humans
  • K562 Cells
  • Multienzyme Complexes/genetics
  • Proteasome Endopeptidase Complex
  • Transcription Factors/genetics
  • Ubiquitins/genetics

Fingerprint

Dive into the research topics of 'Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway'. Together they form a unique fingerprint.

Cite this